Chemical formula: C₁₆H₁₂FN₃O₃ Molecular mass: 313.283 g/mol PubChem compound: 3380
Flunitrazepam interacts in the following cases:
The benzodiazepines, including flunitrazepam, produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. barbiturates, alcohol, sedatives, antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, antiepilectic drugs, hypnotics, skeletal muscle relaxants, antihistamines or narcotic analgesics and anaesthetics.
The anticholinergic effects of other drugs, including atropine and similar drugs, antihistamines and antidepressants may be potentiated.
Patients with impaired renal function should use benzodiazepine medication with caution and dosage reduction may be advisable.
The mutual potentiation between alcohol and flunitrazepam may produce unforeseeable reactions in certain patients. Alcoholic drinks should therefore be avoided while under the influence of this drug.
Patients with impaired hepatic function should use benzodiazepine medication with caution and dosage reduction may be advisable. In rare instances some patients have had elevation of liver enzymes. As with other benzodiazepines, periodic liver function tests are recommended.
In the case of narcotic analgesics, enhancement of euphoria may also occur, leading to an increase in psychological dependence.
Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently.
Cisapride may lead to a temporary increase in the serum levels, and thus sedative effects, of orally administered benzodiazepines due to faster absorption.
The use of benzodiazepines may lead to dependence, as defined by the presence of a withdrawal syndrome on discontinuation of the drug. Tolerance, as defined by a need to increase the dose in order to achieve the same therapeutic effect, seldom occurs in patients receiving the recommended doses under medical supervision. Tolerance to sedation may occur with benzodiazepines, especially in those with drug seeking behaviour.
Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepines. These symptoms can range from headache, tension, muscle pain, restlessness, irritability, insomnia, anxiety, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feelings of motion, metallic taste), numbness and tingling of the extremities, depersonalisation, derealisation, delusional beliefs, hyperreflexia and loss of short term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional states, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in those patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have also been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, flunitrazepam should be terminated by tapering the dose to minimise occurrence of withdrawal symptoms. Patients should be advised to consult with their physician before either increasing the dose or abruptly discontinuing the medication.
Rebound phenomena have been described in the context of benzodiazepine use. Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pre-treatment levels following cessation of benzodiazepines. Rebound phenomena in general possibly reflect re-emergence of pre-existing symptoms combined with withdrawal symptoms described earlier. Some patients prescribed benzodiazepines with very short half-lives (in the order of 2 to 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/rebound symptoms may follow high doses taken for relatively short periods.
It is important to warn against changing to a benzodiazepine with a short duration of action when benzodiazepines with a long half-life are used, as withdrawal symptoms may develop.
Caution should be used in the treatment of patients with acute narrow-angle glaucoma (because of atropine-like side effects).
Flunitrazepam is not recommended as primary therapy in patients with depression and/or psychosis. In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Suicidal tendencies may be present or uncovered and protective measures may be required.
Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. On rare occasions, especially when flunitrazepam was taken with alcohol or CNS active drugs, patients developed unusual or disturbed behaviour of which they had no recollection.
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
Although hypotension has occurred only rarely, flunitrazepam should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral complications. This is particularly important in elderly patients.
Caution in the use of flunitrazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.
Abrupt withdrawal of benzodiazepines in patients with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.
Category C.
Benzodiazepines cross the placenta and may cause hypotonia, respiratory depression and hypothermia in the newborn infant if used in high doses during labour. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided. Withdrawal symptoms in newborn infants have been reported with prolonged use of this class of drugs.
Flunitrazepam is excreted in human breast milk and therefore should not be used when breastfeeding.
Studies have not been performed to assess the potential of flunitrazepam to impair fertility.
Complex behaviours such as “sleep-driving” (i.e. driving while not fully awake after taking a sedativehypnotic, with amnesia for the event) have been reported with sedative hypnotics. These events can occur in sedative-hypnotic naive as well as in sedative-hypnotic experienced persons. These events can occur at normal therapeutic doses, and the risk appears to be increased when sedative-hypnotics are combined with alcohol or other CNS depressants or used at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviours (eg. preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedativehypnotic. As with “sleep-driving”, patients usually do not remember these events.
As with all patients taking CNS-depressant medications, patients receiving flunitrazepam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from flunitrazepam therapy. Abilities may be impaired on the day following use. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of flunitrazepam.
Due to the slight accumulation of flunitrazepam in the plasma, a 2 mg dose of flunitrazepam should not be administered on a daily basis to patients involved in activities requiring concentration during the early part of the day.
Note: Percentages indicate the incidence of adverse reactions in clinical trials.
About 13% of patients experience adverse effects, usually due to the persistence or accentuation of the pharmacological effects of the drug. They are more frequent at higher doses (over 4 mg) and in sensitive or elderly persons.
Common: headache, falling.
Uncommon: asthenia, malaise, collapse, unsteadiness.
Common: hypotension.
Uncommon: tachycardia, orthostatic hypotension.
Common: gastrointestinal upsets, dry mouth.
Uncommon: hiccups
Uncommon: muscle weakness
Common: hangover, tiredness, drowsiness, sleepiness, dizziness, ataxia, confusion, tremor, amnesia, excitation.
Uncommon: daytime sedation, disorientation, slurred speech.
Rare: anxiety, hallucinations, agitation, sleep disturbances, unusual dreams.
Uncommon: skin reactions, sweating, rash, angioedema.
In rare cases, paradoxical reactions such as acute excitation, confusion, agitation, sleep disturbances including unusual dreams, anxiety and hallucinations may occur. If this happens, treatment must be stopped. These reactions may be quite severe with flunitrazepam, and are more likely to occur in the elderly.
Daytime sedative effects, particularly in elderly people, may cause serious domestic accidents.
Paradoxical reactions: Restlessness, irritability, nightmares, inappropriate behaviour, delusions, aggressiveness and psychoses.
Special senses: Double vision.
Urogenital system: Changes in libido.
Central nervous system: Pre-existing depression may be unmasked during benzodiazepine use.
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